Multiple sclerosis (MS) is one of the devastating neurological diseases in young adults that is pathologically characterized by inflammation and demyelination in the brain and spinal cord. More than half of MS patients do not respond well to the current FDA-approved disease-modifying treatments. This lack of response may be due, in part, to the current therapeutics being specifically targeted to the inflammatory phase of the disease, but they do not deliver repair-promoting activity. Therefore, myelin repair may maximize both neurological and functional restoration, and represents a most attractive strategy for developing a new therapy for MS to address this critically unmet medical need. Our interest in developing apolipoprotein E-based remyelinating agents is derived from our unique understanding that 1) apoE is the principal apolipoprotein in the CNS modulating lipid and cholesterol metabolism relevant to myelination; and 2) apoE may affect myelin-forming cells (oligodendrocyte and its precursor cell) proliferation, differentiation and survival during immune attack, inflammation, excitotoxicity, and oxidative stress. Cognosci, Inc. has innovatively designed peptidochemicals to mimic the bioactivities of apoE holo-protein that also display therapeutic efficacy in EAE models of MS. With support of preliminary data in a pilot study, we propose to examine our lead compound COG112 as remyelination-promoting agent in the following aspects: 1) Specific Aim 1: We will verify the potential remyelination-promoting effect of COG112 in a cuprizone-induced demyelination model; 2) Specific Aim 2: We will examine the effect of COG112 treatment on OPC (Oligodendrocyte Precursor Cell) proliferation and differentiation/maturation within the corpus callosum in a cuprizone model; 3) Specific Aim 3: We will examine if COG112 can prevent inflammation-induced oligodendrocyte precursor cell death in a mixed culture of OPC and microglia. The completion of this Phase I grant will generate the preclinical data to establish the utility of our COG compound as a unique, remyelinating agent for the demyelinating disease, MS, either as a supplement to the current immune-modifying therapies, or as an anti-inflammatory itself, the remyelinating properties of COG compounds that we propose in this grant might fill the tremendous medical need for a restorative therapeutic for MS. [unreadable] [unreadable] [unreadable]